Plaster agent and method of preparing same

ABSTRACT

A plaster agent comprising a water impermeable or water semipermeable film (layer a), one tackifier layer (layer b) laminated on one surface of said layer a, and another tackifier layer (layer d) laminated on said layer b through an intermediary knitted fabric having a weight per unit area of 10 to 100 g/m 2  (layer c) comprising hollow fibers having pores extending therethrough in the outer peripheral direction and containing substantially no medicine internally thereof, and at least one of said layer b and said layer d containing a vaporizable or non-vaporizable medicine.

This is a Continuation of application Ser. No. 08/188,769, filed Jan.31, 1994 (now abandoned), which is a divisional of prior parentapplication Ser. No. 08/007,830, filed Jan. 22, 1993 (now U.S. Pat. No.5,336,210), which in turn is a continuation of prior application Ser.No. 07/601,779, filed Oct. 26, 1990 (now abandoned).

TECHNICAL FIELD

The present invention relates to a sustained released pharmaceuticalplaster agent for percutaneous administration, and a method of preparingsame. More specifically, the present invention relates to a plasteragent comprising a knitted fabric comprising specific hollow fibers anda tackifier (or adhesive) layer containing a medicine or drug and afilm, and having a high safety factor, excellent sustained releasabilityand easy handleability, and to a process for efficiently preparing thesame.

The present invention relates to a plaster agent containing nitric acidesters useful for the prophylaxis and amelioration of circulatorydiseases, particularly cardiac diseases such as stenocardia andarrhythmia.

The present invention further relates to an estradiol-containing plasteragent useful for the prophylaxis and amelioration of disordersfrequently observed in women after menopause, such as menopausaldisorders, oestroporosis, and Arzheimer dementia.

The present invention further relates to a buprenorphin-containingplaster agent useful for the relief of pain after surgery, from variouscancers, and from myocardial infarctions, and further, from lumbago,chronic articular rheumatism, trauma, and exodontia, in particular thepain accompanying various cancers, and as an anesthesia aid.

BACKGROUND ART

In the development of pharmaceuticals, simultaneously with thedevelopment of novel compounds having excellent pharmacological effects,various investigations have been made into changes of the dosage formsand an optimization of the administration forms, to to further enhancethe effects of these novel compounds or compounds already used aspharmaceuticals.

For example, to prolong the persistency time of a pharmaceutical with ashort half-life period, which is also a parameter of the effectivepersistency time of a pharmaceutical in the body, the development ofslow release preparations has been made, which will enable thepharmacologically effective ingredient to be absorbed by the human bodyat the minimum effective level or higher and the maximum safe level orlower, i.e., in the effective level region in the blood, over a longtime.

As examples of slow release preparations, there are known preparationsfor a percutaneous absorption such as ointments, sprays and coatings.These preparations are coated by hand onto the skin, and therefore, thedose is not constant, and further, a problem arises in that the ointmentmay adhere to and contaminate the clothing of the patient.

As measures for alleviating these drawbacks, there are known tape agentsand plaster agents which incorporate a predetermined amount of amedicine and are molded to a predetermined size (e.g., see JapaneseUnexamined Patent Publications (Kokai) Nos. 57-116011, 58-134020), andthe use of the method using the tape agent and plaster agent can solvemany problems due to the use of an ointment or spray coating.

Also, when a medicine is percutaneously administered, it is known thatthe ratio of the liver metabolism, which is the phenomenon whereby thepharmacological effect disappears upon receiving the metabolism of thedrug in the liver, can be markedly alleviated compared with the casewhen the medicine is orally administered, and therefore, a tape agentand plaster agent (hereinafter referred to as plaster agent) is anexcellent medicine administration form when the medicine can bepercutaneously absorbed.

Nevertheless, frequent use of such a plaster agent has shown that someproblems arise with the plaster agent of the prior art.

Among such problems, the most frequent is a skin rash generated at thesite at which the plaster agent is plastered to a patient. Generallyspeaking, a sustained release preparation is frequently administered toa patient with chronic diseases, and therefore, the plaster agent isfrequently used over a long term, and thus a skin rash is oftengenerated. Further, a problem arises in that, once a skin rash isgenerated, the afflicted site is susceptible to a growth of the rash.According to statistics, the generation of a skin rash by a plasteragent occurs in 20 to 50% of all patients.

Another problem of the plaster agent is a change of the medicine levelin the blood. The factors causing a change of this level in the bloodare complicated, and include the plaster agent, the skin, and the humanmetabolism functions, and therefore, it is not easy to hold the medicinelevel in the blood at a constant value.

Still another problem concerns the handleability. More specifically, askin rash could be more or less alleviated by making the support of theplaster agent as thin as possible, enhancing the flexibility, and makingthe plaster agent smaller to alleviate a skin rash caused by theplaster, but another problem arises in that it is very difficult toplaster the plaster agent correctly at a predetermined position on thepatient. For example, recently, plaster agents containing as aneffective component nitric acid esters are widely used as therapeuticagents for circulatory diseases such as stenocardia, but theabove-mentioned various problems, particularly the skin rash problems,still remain and, therefore, plaster agents capable of stablymaintaining the concentration of medicines in the blood and not havingthe above-mentioned problems are needed in this field.

On the other hand, as the cause of menopausal disorders, oestoroporosis,and Arzheimer dementia, frequently observed in women after menopause, areduction of estrogen accompanying the menopause is regarded asimportant, and estradiol, estriol and derivatives thereof have beenclinically applied primarily as oral agents and injections.

When estrogen is frequently used, however, side effects such as anincrease in an uterus body cancer are observed, and therefore, it isnecessary to enhance the biological availability (hereinafterabbreviated as BA) during use, as much as possible, at a minimumnecessary dose, while maintaining a stable medicine level in the blood.

Among various estrogens clinically applied, estradiol is one of thenatural estrogens which are inherently synthesized and utilized in theliving body, has a pharmacologically high activity, and althoughconsidered to be the most suitable estrogen for use as a pharmaceuticalfrom the aspect of safety, it has been little used. This is becauseestradiol, when administered orally, is rapidly metabolized in digestiveorgans and the liver and the BA is lowered. To maintain the necessarydrug level in the blood, a large amount of estradiol must beadministered, but this means that an undesirable large amount of harmfulmetabolites by products will be produced in the blood.

The loss of the BA in estradiol can be markedly ameliorated by apercutaneous administration, and a stable drug level in blood can bestill maintained.

Estradiol and derivatives thereof such as esters are known to bepercutaneously absorbed, as disclosed in Japanese Patent Publication(Kokoku) No. 46-5427, Japanese Unexamined Patent Publication (Kokai) No.57-154122, etc. Particularly, the plaster agent disclosed in JapaneseUnexamined Patent Publication (Kokai) No. 57-154122 provides anexcellent improvement of the BA and stabilization of the drug level inthe blood. Nevertheless, although the estradiol-containing plaster agentcompensates for a reduction of estrogen accompanying the menopause, thetherapeutical period can last for several months to several years, andtherefore, a steadfast compliance by the patient is an essentialrequirement. Particularly, in the presence of a plaster agent, althoughan uncomfortable feeling during plastering often exists, a generation ofa skin rash is a serious problem, an insufficient consideration of thispoint has been made in the prior art.

In the prior art as described above, in the case of an oral agent, whichrequires a relatively lower compliance by the patient, the BA is lowerand a generation of side effects is a serious problem, but in the caseof a percutaneous absorption type plaster agent with a high BA and astable medicine level in the blood, the problems of discomfort and ageneration of skin rash remain.

To alleviate the feeling of discomfort, which is a drawback of the priorart, preferably the flexibility of the plaster agent is enhanced as muchas possible and the size thereof made smaller. If the flexibility ismade too high, however, the handling of the plaster agent will becomevery difficult and will reduce the practical applicability thereof. Onthe other hand, since the size of the plaster agent is proportional tothe amount of medicine absorbed, i.e., the medicine level in the blood,if the necessary medicine level in the blood is determined, some meansfor enhancing the percutaneous absorbability is essential when makingthe size of the plaster agent smaller. Accordingly, if an absorptionpromoter is used for enhancing the percutaneous absorbability of themedicine, a problem arises in that a skin rash will occur morefrequently. On the other hand, to alleviate the skin rash, the prior arthas investigated a suitable selection of the tackifier and a reductionof a residual monomer or residual solvent in the tackifier, butfundamentally it is preferable to enhance the water vaporizability orgas permeability of oxygen and carbon dioxide of the plaster agent. Themere enhancement of the water vaporizability or gas permeability of theoxygen, however, may reduce the sealability of the plaster agent, andthus reduce the percutaneous absorbability of the medicine.

It is considered that 80% of patients at the late stage of cancer sufferunendurable pain, and currently 50 to 80% thereof are receiving therapyfor a removal of the pain.

Recently it is considered that late stage cancer patients, substantiallywithout hope from therapy, should pass their remaining time at home withtheir families, and accordingly, an analgesic which can be easilyadministered, has a required effect, and causes little side-effects hasbeen developed.

Generally speaking, a therapy of pain is practiced for three ranks ofthe WHO cancer pain ladder. Namely, when pain is generated, first anon-opium type analgesic is used, and when this is not sufficient, aweak acting opium type narcotic is used, and when even that is noteffective, a strong opium type narcotic is used. The unendurable painsexperienced by patients at the late stage of cancer are included in thesecond step and the third step, and as the drug therapeutical method fora therapy thereof, opium type narcotics are employed.

A representative weak opium type narcotic drug is codeine, and arepresentative strong opium type narcotic drug is morphine. The strengthof the action thereof determines whether the drug is a weak opium typeor a strong opium type, but various side effects are also taken intoconsideration. The side effects of opium type narcotics include nausea,vomiting, sleepiness, constipation, and mental disorders, and further, adrug resistance or habit occurs and diminishes the effects thereofduring usage. In view of the seriousness of such side effects, even inthe analgesic effect of such an opium type narcotic is high, the usethereof must be carefully considered under the present situation.

To solve these problems of opium type narcotics, attempts to alleviatethe side effects by enhancing the analgesic effect by a chemicalmodification of the opium type narcotics have been made for many years.

One of the synthetic analgesics developed from such an investigation isbuprenorphin. Buprenorphin is known to have an analgesic effect 25- to50-fold of that of morphine, and to exhibit little side effects such asmental disorders, etc. Buprenorphin is commercially available as aninjection in Japan, and suppositories have been also developed. Further,in other countries, sublingual tablets are commercially available.Investigations into the development thereof as an ointment have beenalso made.

Nevertheless, in the preparations of the prior art, problems arises inthat the number of administrations is very high, and thus a recurrenceof the pain begins unless the medicine is administered at a correcttime, and further, the administration method if cumbersome. Also,according to the administration method of the prior art, the change inthe drug level in the blood is great.

Buprenorphin is a preferable medicine with fewer side effects thanmorphine, but side actions similar to morphine will be generated by acontinuous usage thereof over a long term.

The mechanism of the generation of side effects has not been clarified,but in view of the dose dependency, it is not preferable to enhance thelevel in the blood more than is necessary. If continuously used for along term under the state in which the level in blood becomes higherthan is necessary, not only is there an increased probability of thisleading to serious side effects, but also there is a fear that, evenwithin a short term, a serious side effect such as respirationsuppression may be induced.

DISCLOSURE OF INVENTION

Accordingly, an object of the present invention is to obviate theabove-mentioned problems of the prior art by providing a plaster agenthaving a high safety factor, excellent slow releasability and easyhandleability, and a process for efficiently preparing same.

A further object of the present invention is to provide a plaster agentcontaining nitric acid esters having a high BA, a stable medicine levelin the blood and having a high level of patient compliance by remarkablylowering the disadvantages, i.e., an uncomfortable feeling and thegeneration of a skin rash, of the conventional nitric acidester-containing plaster agents.

A still further object of the present invention is to provide anestradiol-containing plaster agent having a high BA, a stable medicinelevel in the blood, and having a high level of patient compliance byremarkably lowering the disadvantages, i.e., an uncomfortable feelingand the generation of a skin rash, of the conventionalestradiol-containing plaster agents.

A still further object of the present invention is to provide abuprenorphin preparation which can be administered by a simple methodand has a stable medicine level in the blood.

Other objects and advantages of the present invention will be apparentfrom the following descriptions.

In accordance with the present invention, there is provided a plasteragent comprising a water impermeable or water semipermeable film (layera), one tackifier layer (layer b) laminated on one surface of said film,and another tackifier layer (layer d) laminated on said layer b throughan intermediary knitted fabric having a weight per unit area of 10 to100 g/m² (layer c) comprising hollow fibers having pores extendingtherethrough in the outer peripheral direction and containingsubstantially no medicine internally thereof, and at least one of saidlayer b and said layer d containing a vaporizable or non-vaporizablemedicine.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a preferred embodiment of the present invention, and is asectional view of the sustained release plaster agent obtained inExample 1-1, 2-1, 3-1, 4-1, and 5-1.

In FIG. 1, a is a film layer, b a tackifier layer, c a hollow fiberknitted fabric layer, d a tackifier layer, and e a releasable sheet.

FIG. 2 and FIG. 3 are preferable examples of the texture of the knittedfabric of hollow fibers of the present invention; FIG. 2 comprising 5and 7 longitudinal and lateral loops, respectively, and the knittedfabric of FIG. 3 comprising 4 and 6 longitudinal and lateral loops,respectively.

BEST MODE OF CARRYING OUT THE INVENTION

As mentioned above, according to the first aspect of the presentinvention, the object of the present invention can be accomplished byusing a knitted fabric comprising hollow fibers having pores extendingtherethrough in the outer peripheral portion and containingsubstantially no amount of a medicine, a tackifier layer containing amedicine, and a water impermeable or water semipermeable film, andskillfully utilizing same, to thereby accomplish the present invention.

More specifically, to prevent a skin rash, which is the greatest problemin the use of a plaster agent, and to ensure that no/or substantially noorganic solvent used in the preparation steps remains at least in theplaster agent, and that the skin irritation of the tackifier employed isreduced, the plastered site must not be excessively stuffy, and oxygenmust be supplied to the plastered site to permit the carbon dioxide andammonia gas generated by the skin physiology at the plastered site to bepermeated.

Particularly, it is important to prevent an excessive stuffiness at theplastered site, which is considered to be related to the difficulty of apermeation of, for example, the oxygen, carbon dioxide, and ammonia.

Nevertheless, from the standpoint of permitting a sufficient amount of amedicine to be absorbed percutaneously, which is the inherent object ofa plaster agent, it is essential to allow some stuffiness by sealing theplastered site, and this presents a difficulty in accomplishing theobject of the present invention.

The present inventors made an intensive investigation into the stuffystate at which a skin rash occurs, and the stuffy state required for apercutaneous absorption of the medicine, and found that a percutaneousabsorption of a medicine will not become rapid even if the stuffiness isincreased to the saturated water content of the keratin layer of theskin at the plastered site (at this time superfluous water becomesdroplets at the interface between the skin and the plaster agent), andconversely, the skin rash is increased if the water content of thekeratin layer exceeds the saturation point. Considering from this that apreferable sealability as the plaster agent maintains the keratin layerof the skin at the plastered site in the vicinity of the saturated watercontent, the present inventors made an intensive investigation into thedosage form of the plaster agent, and thus accomplished the presentinvention.

Namely, the present invention provides a plaster agent comprising awater impermeable or water semipermeable film (layer a), one tackifierlayer (layer b) laminated on one surface of said film, and anothertackifier layer (layer d) laminated on said layer b through anintermediary knitted fabric having a weight per unit area of 10 to 100g/m² (layer c) comprising hollow fibers having pores extendingtherethrough in the outer peripheral direction and containingsubstantially no medicine internally thereof, and at least one layer ofsaid layer b and said layer d containing a vaporizable ornon-vaporizable medicine. Surprisingly, with the plaster agent of thepresent invention, even if the amount of skin perspiration variesdepending on the external environment and the movement of the patientplastered with the plaster agent, the water content in the skin keratinlayer at the plastered site can be maintained at substantially the samevalue.

To prevent a skin rash, preferably the amount of residual solvent in theplaster agent is as small as possible, specifically 100 ppm or less,more preferably 50 ppm or less, of the residual amount of the totalsolvent used in the preparation of the plaster agent, based on thetackifier weight. In the plaster agent, most of these residual solventsremain when preparing the tackifier layer from a tackifier solution, andas the method of reducing this residual solvent amount, there may beemployed the method of heating under a high temperature, the method ofvacuum aspiration under heating, the method of washing and extractingthe tacky layer with a solvent such as water, methanol, and ethanol;industrially, the method of heating under a high temperature is mostfrequently employed. Nevertheless, to obtain a tackifier layer with aresidual solvent amount of 100 ppm or less, from a tackifier layer(adhesive layer) having a certain thickness and to be used as thetackifier layer of the plaster agent, it is necessary to employ verysevere drying conditions.

When a medicine is mixed in the tackifier layer, the employment of suchsevere conditions may cause a denaturation or decomposition of themedicine, and frequently pose problems, and when a vaporizable medicineis used as the medicine, the medicine is vaporized at a hightemperature. Therefore, when such a vaporizable medicine is employed,mild rather than conventional drying conditions must be employed, but itis difficult to thereby obtain a safe plaster agent with little residualsolvent therein.

The residual solvent is removed from the tackifier layer at an extremelypoor rate if the thickness of the tackifier layer is large, but isrelatively easily removed if the thickness of the tackifier layer issmall. Accordingly, in the present invention, the tackifier layercontaining a medicine comprises two tackifier layers. The followingplaster agent of the present invention is described with reference tothe processes for the preparation thereof.

The first process for preparing the plaster agent of the presentinvention comprises:

laminating one tackifier layer (layer b), a knitted fabric having aweight per unit area of 10 to 100 g/m² (layer c) comprising hollowfibers having pores extending therethrough in the outer peripheraldirection and containing substantially no medicine, and anothertackifier layer (layer d) on a water impermeable or water semipermeablefilm, in the order of layers a, b, c, and d, and using a tackifier layercontaining a vaporizable or non-vaporizable medicine as at least one oflayer b and layer d.

The second preparation process comprises:

(1) impregnating a laminate having a water impermeable or watersemipermeable film (layer a), one tackifier layer (layer b) containingsubstantially no vaporizable medicine or containing a small amount of avaporizable medicine laminated on a surface of said layer a, and aknitted fabric having a weight per unit area of 10 to 100 g/m² (layer c)comprising pores extending therethrough in the outer peripheraldirection and containing substantially no medicine internally thereofand laminated on said layer b with a medicine solution obtained bydissolving said vaporizable medicine in a volatile solvent on thesurface of said layer c,

(2) heating said laminate while the surface of said layer c is not incontact with the air, to thereby cause a migration of said vaporizablemedicine in said knitted fabric portion to said layer b,

(3) laminating the other tackifier layer, (layer d) which may alsocontain said vaporizable medicine, on said layer c.

The third preparation process comprises:

(1) impregnating a laminate having a water impermeable or watersemipermeable film (layer a), one tackifier layer (layer b) containingsubstantially no vaporizable medicine or containing a small amount of avaporizable medicine laminated on a surface of said layer a, and aknitted fabric having a weight per unit area of 10 to 100 g/m² (layer c)comprising pores extending therethrough in the outer peripheraldirection and containing substantially no medicine internally thereofand laminated on said layer b with a medicine solution obtained bydissolving said vaporizable medicine in a volatile solvent on thesurface of said layer c,

(2) laminating the other tackifier layer (layer d), which may alsocontain said vaporizable medicine, on said layer c to obtain a laminate,

(3) heating said laminate to thereby cause a migration of saidvaporizable medicine in said knitted fabric portion to said layer band/or layer d.

The layer d and the layer b may have the same or different thicknesses.Since the thickness of both layers is thinner than that of the totaltackifier layer of the final plaster agent, and since severe dryingconditions can be applied when no vaporizable medicine is contained, itis easy to bring the residual solvent content to 100 ppm or less, or 50ppm or less. Further, if necessary, the residual solvent can be reducedby applying heat or a vacuum aspiration, or by extraction and washing.Also, as another residual solvent reducing method, the layers d and bmay be prepared by plastering two or more previously prepared thinnertackifier layers.

The first preparation process of the present invention is morespecifically described below.

First, the layer b is laminated on one surface of a water impermeable orwater semipermeable film. The layer b can be laminated thereon by, forexample, coating a tackifier solution on said film, or by pressureadhering said film layer to one surface of the layer b, whereby alaminate comprising the film and the layer b is obtained.

Next, a knitted fabric comprising hollow fibers having pores extendingtherethrough in the outer peripheral direction and containingsubstantially no drug is laminated on the layer b.

Thereafter, the layer d is laminated on said knitted fabric (hereinaftercalled plaster agent raw fabric). The layers d and b may be laminated tothe knitted fabric successively as described above, to give a plasteragent with a more stable shape, but the three layers of the layer d, thehollow fiber knitted fabric, and the layer b also may be laminated atthe same time.

The layer d and the layer b to be used in the first preparation processof the present invention contain a vaporizable or non-vaporizablemedicine in at least one of the layers.

The second and third preparation processes are more specificallydescribed below.

(1) In both of the second and third preparation processes, first alaminate comprising a film, a tackifier layer, hollow fiber knittedfabric impregnated with a medicine solution on the knitted fabricsurface is prepared.

First, the layer b containing substantially no medicine or containing asmall amount of medicine is laminated on one surface of a waterimpermeable or water semipermeable film. The lamination method may becarried out by the coating or pressure adhesion of the layer bseparately prepared as described above. The amount of medicine in thelayer b, in view of the migration of the medicine due to a laterheating, can be made substantially zero, or is only a small amount.

Subsequently, on the layer b, a knitted fabric having pores extendingtherethrough in the outer peripheral direction and containingsubstantially no medicine is laminated by pressure adhesion to obtain alaminate comprising three layers of a film, the layer b, and a knittedfabric (hereinafter called hollow fiber knitted fabric laminate).

Further, a medicine solution containing a vaporizable medicine of thepresent invention is dissolved in a volatile solvent such as acetone,methanol, ethanol, and chloroform (hereinafter called medicinesolution).

Subsequently, the surface of the knitted fabric of the hollow fiberknitted fabric laminate as described above is impregnated with apredetermined amount of a medicine solution. The volatile solvent may beremoved by leaving the laminate to stand under, for example, roomtemperature conditions, but can be also removed under conditions such asheating or cooling, if necessary.

To obtain a plaster agent uniformly containing a medicine, preferablythe knitted fabric is impregnated with a medicine solution, andaccordingly, the method of metering and dropwise adding a medicinesolution, the method of impregnating a hollow fiber knitted fabriclaminate over a predetermined area with a predetermined amount of amedicine solution, the method of metering a medicine solutioncontinuously by a fine cup or pump according to known methods whilemoving the hollow knitted fabric laminate at a constant speed andpermitting a migration thereof when in contact with the knitted fabric,and dropwise adding or spraying same can be employed.

The hollow fiber knitted fabric laminate to be used for impregnation ofa medicine solution in the second and third preparation processes of thepresent invention has a film laminated thereon as described above. Note,even without a lamination of a film, a laminate comprising only theknitted fabric can be impregnated. Nevertheless, when a film islaminated thereon, regardless of the stretchability and the flexibilitypossessed by said knitted fabric, in this case the film not only impartsa good sealability and a prevention of an escape of the medicine to theplaster agent, but also contributes to the retaining of a constant shapeof the knitted fabric, whereby it becomes easier to stably and uniformlyimpregnate said knitted fabric with a medicine solution, and is suitablefor industrial production.

Further, to enhance the uniformity, of the knitted fabrics comprisinghollow fibers as described below, a knitted cloth having only alongitudinal knitting and/or reinforced to maintain a constant shapealso can be used.

Namely, a hollow fiber knitted fabric laminate impregnated with amedicine solution is obtained.

(2) In the second preparation process of the present invention, thelaminate thus obtained is heated while the surface of said knittedfabric is not in contact with the air, to cause a migration of saidmedicine in said knitted fabric portion into the layer b, andthereafter, the layer d, which may also contain said medicine, islaminated on said knitted fabric.

Here, the state wherein the surface of said knitted fabric is not incontact with the air means specifically that said medicine is under astate in which it cannot escape from the laminate. As such a state, forexample, there may be included the rolled state wherein the film is onthe outside and the knitted fabric inside, the folded state, or themethod of covering or packaging the laminate.

Among them, the method of producing a laminate in a long band with awidth of 80 to 1000 mm and rolling the laminate tightly into a roll withthe film on the outside is particularly preferable, because the medicinewill not be able to easily escape therefrom.

The heating conditions are preferably a temperature of 40 to 80° C. forseveral hours to several days. Due to this heating, the medicine in saidknitted fabric portion is migrated into the layer b, to obtain a layer bcontaining a vaporizable medicine and a hollow fiber knitted fabriccontaining substantially no medicine.

Also, due to this heating, the layer b is saturated with the medicinegenerally within 1 to 2 days, and even if the heating time is prolonged,the medicine amount in the layer b is not increased. Of course, theheating conditions can be controlled depending on the kind of themedicine, for example, by elevating the temperature, whereby the degreeof migration into the layer b can be enhanced.

(3) The layer d, which may also contain said varporizable medicine, islaminated on said knitted fabric of the laminate thus obtained by apressure adhesion, to obtain a plaster agent raw fabric.

Accordingly, the plaster agent raw fabric obtained by the first to thirdpreparation processes of the present invention may be cut, if necessary,and then sealed and packaged to form a plaster agent as the preparation.When it is necessary to accelerate the medicine percutaneous absorptionimmediately after plastering said plaster agent onto the patient, tothereby expedite the effect by increasing the medicine level in theblood, the sealed and packaged plaster agent is heated at a temperatureof 40 to 80° C. for several hours to several days, as required. If theheating conditions are approximately the same as the heating conditionsused for the medicine impregnated knitted fabric laminate, theconcentrations in the layer d and the layer b will become substantiallythe same. Further, as the heating conditions are made milder, theinitial medicine concentration in the layer d becomes smaller than themedicine concentration in the layer b, whereby the effect on the levelin the blood becomes slower, and thus the medicine is released moreslowly. Therefore, according to the preparation process of the presentinvention, it is easier to design a preferable sustained releasepreparation.

Instead of cutting the plaster agent raw fabric followed by sealingpackaging before the heating treatment, it is also possible to directlyheat the plaster agent raw fabric to cause a migration of the medicinein the layer b, in an necessary amount, to the tacky layer d.

(2)′ Further, according to the third preparation process of the presentinvention, the layer d, which may also contain said vaporizablemedicine, is laminated on the hollow fiber knitted fabric laminateobtained as described above in (1), to obtain a laminate, and (3)′ thelaminate obtained is then heated to cause a migration of the medicine insaid knitted fabric portion into the layer b and/or the layer d, andthus a plaster agent raw fabric is similarly obtained.

Note, the heating conditions in this case are the same as in the secondpreparation process as described above.

Instead of obtaining the plaster agent raw fabric by migrating, uponheating, a medicine in the knitted fabric portion into the layer band/or the layer d, after the plaster agent raw fabric is cut andseal-wrapped, the medicine in the knitted fabric portion may be allow tomigrate into layer b and/or layer d.

According to the second and third preparation processes, for example,the migration into the layer d is the last step of the preparationsteps, whereby a control of the sustained releasability of thevaporizable medicine can be easily attained. Further, when the layer dis laminated after a migration of the medicine in the knitted fabricportion into the layer b, an advantage is gained in that the laminationis carried out because there is no affect by the medicine.

In the present invention, the contents of the medicine contained in thelayer b and the layer d may be different, and further, theircompositions and additives may be different.

Also, in the present invention, when using the layer d and the layer bwith specific thicknesses, and when the knitted fabric of hollow fibershas a specific weight per unit area, a suitable number of voids willoccur around the hollow fiber knitted fabric provided at the center ofthe plaster agent obtained, and through a mutual interaction between thevoids and the hollow fibers having pores extending through in the outerperipheral direction, a plaster agent is preferably provided which hasno excessive stuffiness at the plastered site and gives a goodsealability, whereby a medicine is absorbed as intended by the presentinvention.

Also, by controlling the loop number of the knitted fabric of hollowfibers, the layer b and the layer d are in good contact with each otherwhereby, even when a medicine is not contained in the layer d, themedicine is migrated from the layer b to the layer d and there released,to thus obtain a preferable sustained release effect.

The plaster agent raw fabric of the present invention can be any desiredsize of 3 to 100 cm², and can be cut to any desired shape such ascircular, square, or rectangular, and can be packaged according to aknown process, to thereby form a plaster agent for medical use.

The hollow fibers to be used in the present invention must have poresextending therethrough in the outer peripheral direction, and containsubstantially no medicine. Here, the hollow fibers having poresextending therethrough in the outer peripheral direction are preferablyhollow fibers having fine pores, which are scattered over the wholecross-section of the hollow fiber and arranged in the fiber axisdirection, and at least a part of which communicate with the hollowportion.

The external shape and the shape of the hollow portion in the lateralcross-section of the hollow fiber of the present invention may be asdesired. For example, the external shape and the hollow portion areapproximately circular, either of the external shape and the hollowportion is approximately circular and the other deformed, and theexternal shape and the hollow portion are both similar or havedissimilar deformed shapes. The size of the external shape is notparticularly limited.

The thickness of such a hollow fiber is preferably 0.2 to 20 denier,preferably 1-5 denier or more. When the thickness is 20 denier or more,the skin irritation is very high, but a hollow fiber with a thickness of0.2 denier or less has a poor handleability.

The hollow ratio of the hollow fiber of the present invention may be asdesired, but particularly preferably is 5% or more, and the ratio of thepores extending through in the outer peripheral direction in fiberlateral cross-sectional area excluding the hollow portion is preferably0.01 to 70%, more preferably 0.01 to 50%, most preferably 1 to 50%.

In the present invention, the hollow fibers must be in the form of aknitted fabric. The knitted fabric may be constituted primarily of thehollow fibers as described above, but fibers other than such hollowfibers also can be partially mixed therein, as long as the effectintended by the present invention is not impaired.

The forms of fabric may be broadly classified into woven fabrics,knitted fabrics, and nonwoven fabrics. Among these fabrics, wovenfabrics have been widely used in the art for medical use such as gauzeand an adhesive plaster. As indicated above, of the several differentforms of fibers generally used in the art, the hollow fibers used in thepresent invention must be in the form of a knitted fabric. This isprimarily because woven fabrics have a good dimensional stability, andare easily handled. Nevertheless, woven fabrics give a greater skinirritation when formed into plaster agents. In contrast, knitted fabricsgive little skin irritation, and a thin knitted fabric has even lessskin irritation. Particularly, a thin knitted fabric comprising hollowfibers having pores extending therethrough in the outer peripheraldirection is extremely flexible and causes substantially no skinirritation. Surprisingly, substantially no flexibility will be lost evenwhen a thin film with little stretchability is laminated on such knittedfabric. This may be because a delicate allowance within the fibertexture absorbs external stress.

The weight per unit area of the knitted fabric of hollow fibers of thepresent invention is preferably 10 g/m² to 100 g/m². If the weight perunit area is too large, the sealability of the plaster agent isworsened, and thus the percutaneous absorbability of the medicine willbe poor. On the contrary, if the weight per unit area is too small,various problems will arise, i.e., if the weight per unit area is toosmall, the knitted fabric is difficult to handle and an excessivesealability sometimes occurs as the weight per unit area becomessmaller.

Further, the knitted fabric of the hollow fibers of the presentinvention is preferably knitted so as to have loop numbers of 3 to 22/cmin the longitudinal and lateral directions, with the sum thereof being15 to 37/cm, when a frame with a square opening of 1 cm×1 cm at thecenter thereof is applied on the knitted fabric and the loops of theknitted fabric are counted.

Regarding the texture of the knitted fabric, reference can be made to“Meriyasu Gijutsu Hikkei” (Society of Fiber Machinery of Japan, Aug. 10,1982). Note, FIG. 6.2 on page 199 and FIG. 4.17 on page 109 of thisJournal are shown as FIG. 2 and FIG. 3. In FIG. 2, the numbers of loopsin the longitudinal and lateral directions are counted as 7 and 5,respectively, and in FIG. 3, there are 4 loops in the longitudinaldirection and 6 in the lateral direction. In the case of FIG. 2 and FIG.3, the loop number per unit length is not clear, because practicaldimensions are not given, but the sums of the loop number at thelongitudinal and lateral direction were 24/cm and 20/cm when length oflongitudinal and lateral is 0.5 cm×0.5 cm.

In the present invention, if the sum of the loop number of the knittedfabric is 37/cm or more, in addition to the problem of a poorsealability of the plaster agent, the stability of the preparation whenthe plaster agent is plastered onto the patient will be worsened,whereby an interlayer peeling will occur between the tackifier layer andthe fabric.

Particularly preferably, the sum of the loops is 26/cm or less. If thesum of the loops is 15/cm or less, when the weight per unit area of theknitted fabric is relatively smaller, the layer b will extrude throughthe mesh of the knitted fabric, whereby the tackifier will undesirablystick to machinery and workers handling the hollow fiber knitted fabriclaminate. On the other hand, when the weight per unit area of theknitted fabric is relatively larger, the voids around the hollow fiberknitted fabric in the plaster agent become too large, and thesealability becomes poor. Even if the number of loops is the same, bychanging the number of hollow fibers used for making one loop, theweight per unit area can be freely changed, but in the presentinvention, the weight per unit area is preferably 10 to 100 g/m², andthe sum of the loops is preferably 15 to 37/cm, most preferably,theweight per unit area is 20 to 60 g/m², and the sum of the loops is 15to 26/cm. Particularly, by using a knitted fabric obtained by stretchinga hollow fiber knitted fabric so that the number of loops in thelongitudinal direction is 1.5-fold or more that in the lateraldirection, instead of the same number of loops in both the longitudinaland lateral directions, the handleability of the hollow fiber knittedfabric is improved to a great extent, and thus a plaster agent having astable quality and an excellent sustained releasability is obtained.

As the material of the hollow fiber usable in the present invention, anymaterial including, for example, polyesters such as polyethyleneterephthalate; polyolefins such as polyethylene, polypropylene;polyamides such as nylon 6, nylon 66; polyurethane, cellulose acetate,polyacrylonitrile, polyvinyl chloride, polyvinyl acetate can be chosen.Among them, polyesters are preferred, and particularly, polyethyleneterephthalate is preferred, because of it's high safety to human beings,excellent stability against heat, light and humidity, little muturalinteraction wih medicine, difficulty to be modified by a solvent used inthe impregnation of a medicine solution to a hollow fiber.

The hollow fiber usable in the present invention can be preparedaccording to the processes described in, for example, JapaneseUnexamined Patent Publication (Kokai) Nos. 56-20612, 56-20613, and56-43420.

In the present invention, hollow fibers also can be used by combining aplurality of different materials or forms thereof, or using differenthollow ratios.

In the present invention, the vaporizable medicine refers to a medicinewhich is vaporizable when applied to the human body, and therefore, amedicine which is inherently solid and vaporized by sublimation, orwhich is inherently liquid and is vaporized in that state, may beemployed. Examples of such medicines include nitric acid esters such asisosorbide nitrate, nitroglycerine as typical examples, but also therecan be exemplified guayazulene, menthol, camphor or salicyclic acidesters such as methyl salicyrate. The amount of the medicine used may besuitably determined depending on the potency of the pharmacologicalaction of the medicine and absorbability by the skin, but is preferably0.1 to 20% by weight based on the total weight of the tackifier. Thismedicine may exist in and be mutually mixed with the tackifier layer, ora part thereof may be precipitated as crystals. When the medicine isnitric acid esters, the preferable amount is 8 to 18% by weight and thenitric acid ester-containing plaster agent is preferably prepared by theabove-mentioned second or third preparation method, especially the thirdpreparation method.

As the medicine in the present invention, a non-vaporizable medicine mayalso be employed. The non-vaporizable medicine as mentioned in thepresent invention refers to a medicine which has little vaporizabilitywhen applied to the human body. Among such medicines, percutaneousabsorbable medicines are preferred.

As such medicines, there can be included, for example, hormones such asestradiol, progesteron and derivatives thereof; analgesics such asmorphine, buprenorphin and derivatives thereof; cardiac agents such aschronidine, nifedipine; etc. These are not limitative, and anynon-vaporizable, particularly a non-vaporizable and percutaneousabsorbable medicine, may be included. The mount of medicine employed maybe suitably determined depending on the potency of the pahrmacologicalaction of the medicine employed, and absorbability by skin, etc., but ispreferably 0.1 to 20% by weight based on the total weight of thetackifier. Such a medicine may also be present when mixed with tackifierin the tackifier layer, or a part thereof may be precipitated ascrystals.

As the tackifier usable in the present invention, conventional pressuresensitive tackifiers may be employed and can be chosen from among, forexample, rubbery viscous compositions composed mainly of, for example,silicone rubber, polyisoprene rubber, styrene-butadiene copolymerrubber, acrylic rubber, natural rubber; vinyl viscous compositions suchas polyvinyl alcohol, ethylene-vinyl acetate copolymer; viscouscompositions composed mainly of silicone tackifier, polyurethaneelastomer, polyester elastomer, polybutadiene elastomer; acrylic resins;and so on. Among them, acrylic resins are preferred, and particularlyfrom the standpoint of less skin irritation, adequate tackiness,adhesiveness, a high degree of internal cohesive force, and an excellentsolvent resistance, an acrylic resin comprising a copolymer of (1) atleast 80 to 98 mole % of an alkyl (meth)acrylate with an alkyl grouphaving 4 or more carbon atoms and (2) 2 to 20 mole % of acrylic acidand/or methacrylic acid is particularly preferred. Examples of the alkyl(meth)acrylate with an alkyl group having 4 or more carbon atoms includebutyl (meth)acrylate, amyl (meth)acrylate, hexyl (meth)acrylate, heptyl(meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl(meth)acrylate, 2-ethylhexyl (meth)acrylate and the like. Thesetackifiers may be employed either singly or in a combination of two ormore kinds thereof.

In the present invention, these tackifiers can be also combinedcorresponding to the kind of medicine, and by using a combination of atackifier having a higher compatibility for the layer b, and a tackifierhaving a less compatibility with the medicine but giving little skinirritation for the layer d, a plaster agent giving little skinirritation and having an excellent slow releasability can be obtained.

The preferable thicknesses of the layer d and the layer b in the presentinvention are 5 to 100 μm. If the thickness of the tacky layer is large,the amount of residual solvent is greatly increased, and therefore, mostpreferably the thickness is 50 μm or less. On the contrary, if the tackylayer becomes thinner, the adhesion to the human skin and to the knittedfabric and film will be lowered, to lower the stability during usage ofthe plaster agent, and thus a preferable thickness of the tacky layer is5 μm or more, particularly 10 μm or more. Regarding the layers b and d,the thickness of the layers b and d are preferably 10 to 50 μm and 10 to100 μm, respectively, and preferably the layer b is thinner than thelayer d.

As the film to be used in the plaster agent of the present invention,those which satisfy the requirements of obstructing an escape of themedicine, do not lower the adhesion to the skin and do not causediscomfort when adhered to the skin are preferred, and are exemplifiedby films of polyolefins such as a polyethylene, polypropylene;polyesters such as polyethylene terephthalate; polyamides such as nylon6, nylon 66; polyvinyl alcohol, vinylidene chloride, polyurethane, andethylene-vinyl acetate copolymer, and rubber. These films my be usedeither alone, when combined, or as a laminate.

Among these films, particularly an extremely thin polyethyleneterephthalate with a thickness of 4.9 μm or less is preferable, toensure a stability against heat and light, a good absorption of themedicine, and absence of a mutual interaction with the medicine.(Hereinbelow, this film is called “packing film” in the presentinvention.)

In the present invention, a peeling sheet also may be provided on thetackifier layer. The peeling sheet may be a conventional sheet, asexemplified by a paper coated on the surface with a releasable layer.

When estradiol or the derivatives thereof is contained, as a medicine,in the plaster agent of the present invention, the estradiol or thederivatives thereof is preferably contained in the above-mentionedacrylic tackifier layer in an amount of 0.5 to 5% by weight.

Here, estradiol or the derivatives thereof refer to natural estrogen,synthetic estrogen and derivatives thereof, as exemplified by estradiol,estradiol benzoate, estradiol dipropionate, estradiol valerate, andethynyl estradiol (hereinafter, in the present invention, theseestradiols are abbreviated as E₂).

The concentration of E₂ in the acrylic tackifier layer is an importantfactor in the percutaneous absorption of the E₂ containing plaster agentfinally obtained. At a concentration of less than 0.5% by weight, asufficient percutaneous absorbability can not be obtained, and thepercutaneous absorbability becomes substantially proportionallyenhanced, as the concentration becomes 0.5% by weight or more, with theincrease of the concentration. When the concentration is higher than 10%by weight, however, a further increase in the percutaneous absorbabilitydoes not substantially occur, but rather a remarkable crystallization ofthe E₂ in the tackifier layer occurs, and as a result, the percutaneousabsorbability is reduced. Thus, at a concentration of higher than 10% byweight, the percutaneous absorbability becomes unpreferably small andthe adhesive force of the preparation obtained becomes undesirably poor.The preferable concentration is 1 to 5% by weight.

Moreover, the present inventors frequently found that a plaster agentstored in the form of a known packed plaster agent, in an aluminum bagor the like where the E₂ concentration in the tackifier layer is 0.5 to5% by weight, had a poor percutaneous absorbability, and as a moreserious problem, that the percutaneous absorbability was changed to agreat extent.

The present inventors made an intensive investigation into the cause ofsuch a change with a lapse of time, by enhancing the percutaneousabsorbability of E₂, discovered that the crystallization of E₂ willmarkedly change depending on the ambient humidity, and searched for ameans to prevent this change. As a result, it was found that (1) theequilibrium water content in the acrylic tackifier, which changesdepending on the temperature and humidity, is 0.7 to 1.5% under a roomtemperature, and that a small amount of water may be sometimes used in apart of the steps for preparing the acrylic tackifier. In that case, thewater content in the tackifier layer obtained can exceed 2.0% if thedrying conditions when obtaining the tackifier layer by coating anddrying the acrylic tackifier are mild. Accordingly, if a tackifier layerwith such a water content is used, a crystallization of E₂ cannot beprevented even if the plaster agent obtained is double or tripleanti-humidity packaged with aluminum packaging, and when the watercontent is different, the extent and speed of the crystallization willdiffer in correspondence thereto, whereby a varying of the percutaneousabsorbability occurs.

In the present invention, by lowering the water content in the tackifierlayer to 0.5% by weight or less, a crystallization of E₂ becomesdifficult, and further, by lowering the concentration of E₂ in thetackifier layer to 5% by weight or less, preferably 3.5% by weight orless, it becomes possible to prevent a change of the absorbability dueto a precipitation of the crystals from the plaster agent with a lapseof time.

If the concentration of E₂ is 0.5% by weight or less, however, thepercutaneous absorbability becomes extremely low, and thus thepharmacological effect is not substantially exhibited.

Therefore, in the present invention, an E₂ concentration of 0.5 to 5% byweight and a water content of 0.5% by weight are employed, butpreferably, when the E₂ concentration (% by weight) is represented byC_(E) and the water content (% by weight) by C_(W), a water contentrepresented by the following formula is employed, to thereby provide avery stable plaster agent:

C _(W)≦0.6−0.1×C _(E) (with the proviso that

C _(W) is 0.5 or less).

As the method of providing the water content of 0.5% by weight or lowerin the tackifier layer of the plaster agent of the present invention,there may be employed:

(1) The method in which the water content in said tackifier layer ismade 0.5% by weight or less by using a sufficient temperature and timein the drying step when making the estradiol containing acrylictackifier layer to be used in the present invention, and then, to avoidhumidification, quickly forming same into a preparation followed bypackaging in an anti-humidity package such as an aluminum bag, under adehumidified environment;

(2) the method in which the tackifier layer obtained by a conventionalmethod is once placed as such, or after processing, under a humidityreduced environment at a mild heating of 40 to 80° C., or under areduced pressure, to reduce the water content to 0.5% by weight or less,followed by packaging in an anti-humidity bag such as aluminum bag;

(3) the method in which the plaster agent formed into a preparation isplaced under the humidity reduced in environment at a mild heating of 40to 80° C., or under a reduced pressure, to reduce the water content to0.5% by weight or less, followed by packaging in an ant-humidity bagsuch as aluminum bag;

(4) the method in which the plaster agent formed into a preparation isstored together with known drying agents such as silica gel, alumina,and phosphorus compounds, in an anti-humidity bag such as aluminum bagor box. When the above-mentioned methods (1), (2), and (3) are employed,although the water content is made 0.5% by weight or less with mucheffort, the plaster agent for medical use is placed under varioustemperatures and humidities, and stresses and a slight water permeationmay occur, whereby variances of the quality will occur.

As the anti-humidity packaging material, aluminum foil or a plasticpackaging material applied with an aluminum vapor deposit well known inthe art may be employed. As the plastic, Teflon, polyvinylidenechloride, polyethylene, high density polyethylene, polyisobutylene,butyl rubber, hydrochloric acid rubber are preferable, but according tothe results of an investigation by the present researchers, thethickness of the aluminum foil or the aluminum of aluminum vapordeposition was found to be important. Packaging materials are generallydesigned from the viewpoint of economy, in addition to a good appearanceand handling, and the thickness of the aluminum is frequently 7 μm orless. For the purpose of the present invention, however the thickness ofaluminum is preferably 8 μ or more, more preferably 9 μ or more. Anothermode of anti-humidity packaging is a packaging canned in tinplate, etc.,but this is inconvenient when carried and has a problem of economy, andtherefore, is not recommended.

One cause of a skin rash at the site plastered with the plaster agent isthe residual solvent remaining in the tackifier layer, and thus,although it is known in the art that various organic solvents used forthe preparation of the tackifier layer remain in the obtained tackifierlayer, it is important to control the amount of the residual solvent,for a reduction of the generation of a skin rash. According to aninvestigation made by the present inventors, to significantly reduce theskin rash, the amount of the residual solvent is preferably 100 ppm orless, more preferably 50 ppm or less. The above-mentioned methods (1),(2), (3), (4) can be employed to lower the water content of the presentinvention, whereby the residual solvent also can be preferably lowered.

In the acrylic tackifier layer containing the E₂ of the presentinvention, it is desirable to use a polyvinyl pyrrolidone. This isbecause, even though the E₂ is contained at about 3% by weight, at whichthe percutaneous absorbability is optimum, the percutaneousabsorbability is still too low, and more important, a precipitation ofthe E₂ as crystals in the tackifier layer occurs with a lapse of time,whereby the percutaneous absorbability is changed. The present inventorsmade an intensive investigation into a means for enhancing thepercutaneous absorbability of the E₂, and preventing such a change witha lapse of time, and found that it is effective if a polyvinylpyrrolidone is contained in an amount of 0.5 to 15% by weight.

The polyvinyl pyrrolidone according to the present invention refers to apolymer a N-vinyl-2-pyrrolidone having a molecular weight of about100,000 or more (hereinafter abbreviated as PVP in the presentinvention).

When the polymerization degree of PVP is smaller than this, when PVP isdissolved in the dope (solution of a tackifier dissolved in an organicsolvent) when making an acrylic tackifier layer, the dope will be gelledand it will become difficult to prepare a tackifier layer having auniform thickness. Further, specks of the gelled PVP will exist in alarge number in the obtained acrylic tackifier layer, and will have anadverse affect on the effect of promoting a percutaneous absorption ofthe E₂.

A small amount of other monomers or polymers may be copolymerized withthe PVP of the present invention, provided that the effect of thepresent invention still can be obtained.

The PVP is contained in an amount of 0.5 to 15% by weight based on thetackifier in the acrylic tackifier layer. When the amount is more than15% by weight, the adhesion of the tackifier layer becomes poor, andwhen less than 0.5% by weight, a required E₂ percutaneous absorptionpromoting effect and crystallization preventive effect cannot beobtained.

The E₂ percutaneous absorption promoting effect and the crystallizationpreventive effect are not limited by the E₂ concentration in thetackifier layer, but the effects obtained tend to become greater whenthe concentration of PVP is higher. With a concentration of 10% byweight or more, the increased effect is lessened, and thus thepreferable range is 0.5 to 5% by weight.

In the estradiol-containing plaster agent of the present inventioncontaining PVP in the tackifier layer, by incorporating a specificamount of PVP, a crystallization of E₂ is prevented, and thus anexcellent percutaneous absorbability is obtained. The present inventorshave further found that a plaster agent which is stable for a longerterm can be obtained by maintaining the water content in the plasteragent at a certain level or lower.

Therefore, in the plaster agent of the present invention, the watercontent in the plaster agent is preferably 1% by weight or less, morepreferably 0.7% by weight or less. This predetermined amount of watercontent is incorporated by controlling the drying temperature and time,etc., during the preparation of plaster agent, but for maintaining sameover a long term, by further preparing the plaster agent with a watercontent of 0.2% by weight or less, and sealing same under the dry statewithin a packaging material having a humidity resistance, theabove-mentioned water content of 1% by weight or less can be obtained.

In this case, the presence of a drying agent such as silica gel is alsoeffective.

For such a preparation of the present invention to give a desiredpercutaneous absorbability, preferably the sealability is maintainedsuch that the water content in the preparation is 0.9% or more, morepreferably 1.0% or more, when the preparation is plastered to a patient.

Thus, in the present invention, the E₂ and an acrylic tackifier aremixed, preferably with PVP, in the presence of a solvent, and theresultant acrylic tackifier dope is coated by a conventional coatingmachine and dried, preferably by a specific water content, to remove thesolvent, whereby a tackifier layer having a thickness of 5 to 100 μm andcontaining the E₂ is obtained.

Using the acrylic tackifier layer containing the E₂ thus obtained, andestradiol plaster agent raw fabric having a specific thickness andcomprising an acrylic tackifier layer having the E₂ of the presentinvention is provided according to the above-mentioned first productionprocess.

This plaster agent raw fabric can be used as E₂ containing plaster agentby cutting and appropriate size and shape.

In the plaster agent containing buprenorphin to the present invention,in view of the above-mentioned drawbacks of the prior art, a preparationfor administering buprenorphin by a simple administration method, and bya method which provides a stable drug level in the blood and is verysafe is provided.

The buprenorphins of the present invention refer to free buprenorphin orpharmaceutically acceptable salts such as buprenorphin hydrochloride andthe like. Hereinafter, in the present invention, such buprenorphins areabbreviated as BN.

In the present invention, in such a tackifier, the BN is preferablycontained in an amount of 1 to 20% by weight, preferably 5 to 15% byweight, based on the total amount of tackifier.

Generally speaking, as the drug concentration in the pressure sensitivetackifier becomes higher, the releasability of the medicine from theplaster agent is enhanced, but in the case of BN, although the BNreleasability is enhanced at a content ratio of 1 to 10% by weight inthe tackifier, the BN releasability will be lowered when it exceedsabout 10% by weight. Particularly, with a content ratio of less than 1%by weight or more than 20% by weight, the plastering area of thepreparation for obtaining the BN level in blood for exhibiting arequired pharmacological effect becomes larger in a human being in theformer, and in the latter, an increased skin irritation and loweradhesive force due to a crystallization of buprenorphin may occur,whereby the superiority thereof to other administration modes of BN islost.

On the other hand, the size of the plaster agent for ensuring littleskin irritation is about 100 cm² or less. Also, from the viewpoint ofthe handleability of the preparation, an extremely small preparationcauses problems, and a preferable size of the plaster agent is 3 cm² ormore, preferably 20 to 100 cm².

In the plaster agent according to the present invention, two tackifierlayers, layers d and b, are used as the tackifier layer. Therefore, byincorporating the BN only in the layer d, or by incorporating a higherconcentration of the BN in the layer d than in the layer b, the amountof the BN used in the plaster agent can be reduced and, therefore, a BNplaster agent having small side effects, even used for a long time, canbe provided.

As a production method of the plaster agent containing BN according tothe present invention, the above-mentioned first production method maybe mentioned.

Each tackifier layer of the present invention preferably has a thicknessof 10 to 100 μm. When the thickness of the tackifier layer is larger, itbecomes difficult to remove the solvent employed in preparation of thetackifier layer, thereby posing a problem of a residual solvent. Thatis, this residual solvent is a major cause of a skin irritation such asa skin rash. Also when the tackifier layer is too thick, the amount ofthe tackifier layer exposed on the cut surface of the plaster agentobtained becomes larger, whereby external foreign matter will adherethereto when plastered for a long time to give a dark contaminatedstate, which will appear unpleasant to the patients. A preferablethickness is 100 μm or less. On the contrary, when the tackifier layeris smaller than 15 μm, the adhesiveness force to the human skin will begreatly lowered, and particularly, if 10 μm or less it becomes difficultto keep the plaster agent on the human skin stably for a long time. Aparticularly preferable thickness is 10 to 60 μm.

As the method of reducing the residual solvent, a stronger drying iscarried out during preparation of the tackifier layer, i.e., the dryingtemperature ×drying time is greater, but in the case of BN it is notpreferable to make the drying temperature higher because of the poorthermal stability of BN, and thus to make the residual solvent easilyvolatilizable, preferably the tackifier layer is as thin as 10 to 60 μm.

Also, the BN content in the tackifier layer is important. BN content inthe present invention refers to that in the whole layer of the plasteragent and to exhibit an analgesic effect by a slow release for asufficient time, in a human being, the BN content is preferably 0.6 mgor more. On the other hand, 30 mg or more is not preferable from thestandpoints of an excessive cost and poor safety. A particularlypreferable range is 1 to 15 mg.

The clinical dose of BN is small, and the medicine is percutaneouslyabsorbed with relative ease, in view of the dose. Particularly, a freeform without a formation of salt can be easily percutaneously absorbed,and the object can be sufficiently achieved with the plaster agent asdescribed above.

Nevertheless, particularly when the present plaster agent is used forpain removal for patients at the late stage of cancer, since it is usedat all times, and for a long term of several years, the plaster agentmust be small and yet give a high level dosage in the blood, to obtain asufficient pain removal.

Accordingly, it is also desirable to use an absorption promoter in theplaster agent of the present invention. Examples of such a promoterinclude:

(1) surfactants such as nonionic surfactants, amphoteric surfactants,anionic surfactants, cationic surfactants, etc. including polyoxetylenehardened castor oil 10 (hereinafter polyoxyethylene hardened castor oilis abbreviated as HCO), HCO-40, HCO-50, HCO-60, polysolvate 40(hereinafter polysolvate is abbreviated as Tween^(R)), Tween^(R)-60,Tween^(R)-65, Tween^(R)-80, sorbitane trioleate, sorbitanepolyoxyethylene(160)polyoxypropylene(30)-glycol monostearate, sorbitanemonopalmitate, sorbitane monolaurate, glycerine monostearate, sodiumlaurylstearate, lauromacrogall, sorbitane sesquioleate, benzalkoniumchloride, benzetonium chloride,

(2) amines such as monoethanolamine, diethanolamine, triethanolamine,diisopropanolamine, triisopropanolamine,

(3) inorganic alkaline compounds such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, sodium hydrogen carbonate,

(4) polyvinyl pyrrolidine, propylene glycol, benzyl alcohol, menthol,isosorbide nitrate, dodecylazacycloheptane-2-one, ethanol.

The absorption promoter is preferably used in an amount of 0.1 to 5% byweight based on the tackifier. If less than 0.1% by weight, a sufficientabsorption promoting effect cannot be obtained, and if more than 5% byweight, the adhesion of the plaster agent is lowered. Such an absorptionpromoter may be used alone or as a mixture of one or two or more kindsthereof.

Among such absorption promoters, amines and/or inorganic alkalinecompounds are particularly effective when the BN is buprenorphinhydrochloride, and when used in an amount of equivalent mole or lessrelative to the buprenorphin hydrochloride. Also, when ethanol is usedas the absorption promoter, by providing a reservoir of ethanol in theplaster agent and making the dosage form such that ethanol can bereleased at a substantially constant speed from such a reservoir, thepercutaneous absorption amount of BN can be controlled.

The present plaster agent containing BN obtained as mentioned above hasan excellent handleability, provides a stable BN level in the blood, andhas a high safety factor.

The plaster agent of the present invention also may contain, forexample, absorption aids, dissolution aids, diffusion aids, and fillers,if necessary.

As the absorption aid or the diffusion aid usable in the presentinvention, there can be employed, for example, surfactants such assodium laurylsulfate, sodium dodecylbenzenesulfonate, sodiumalkyldiphenyl ether disulfonate, dioctylsulfosuccinate,polyoxyalkylphenyl ether sulfate ammonium salt; alcohol such as ethanol,glycerine, diethylene glycol, propylene glycol, polyethylene glycol,higher fatty acid alochol; dimethyl sulfoxide and alkylmethylderivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide,lanolin, allantoin, squalene, carbopol, diisopropyl adipate, laurylpyrroglutamate, ethyl laurate, methyl nicotinate, sorbitol, pyrrolidonederivatives such as polyvinyl pyrrolidone, dodecyl pyrrolidone, methylpyrrolidone, olive oil, castor oil, fluid paraffin, petrolatum, gelatin,amino acid, benzyl nicotinate, 1-menthol, camphor,dodecylazacycloheptane-2- one, and the like.

When such a diffusion aid is incorporated together with a vaporizablemedicine in a medicine solution, and impregnated to the hollow fiberknitted fabric laminate, even in the case of an insufficient migrationto the tacky layer, the migration can be preferably enhanced.

As the filler, there can be included water, titanium oxide, calciumcarbonate, gypsum, calcium silicate, aluminum silicate, diatomaceousearth, carbon black, red iron oxide, various dyes and pigments, fluidparaffin, petrolatum, lactose, perfumes, deodorants, powder or moldingof synthetic resins such as polyethylene, polypropylene, polyester, andpolystyrene.

Industrial Applicability

As explained above, the plaster agent according to the present inventionhas a structure such that the knitted fabric having a weight per unitarea of 10 to 100 g/m² (layer c) comprising hollow fibers having poresextending therethrough in the outer peripheral direction and containingsubstantially no medicine internally thereof is placed between tackifierlayers (layers b and d), wherein at least one of said layer b and saidlayer d containing a vaporizable or non-vaporizable medicine. Therefore,the resultant plaster agent can be utilized such that the desiredpercutaneous absorbability (sustained release) can be provided and thatthe generation of the skin rash can be remarkably prevented, since theplaster agent gives a very moderate roughness to the portions to whichit is applied but an excessive stuffiness is prevented. Furthermore,since the plaster agent according to the present invention uses thespecified knitted fabric comprising hollow fibers is used, the plasteragent itself is very flexible, does not substantially irritate the skin,and while maintaining the necessary sealability, has only a small amountof residual solvent, an excellent handleability, and a high safety.

EXAMPLE

The present invention is further described in more detail with referenceto Examples. All “parts” in the Examples are parts by weight, and thecharacteristics shown in Examples were measured according to thefollowing methods.

(i) Water absorption speed test method (according to JIS-L 1018

Fibers were formed into a knitted fabric, which was washed with a 0.3%aqueous solution of an anionic detergent Zab (Kao Sekken) by an electricwashing machine for domestic use at 40° C. for 30 minutes, repeatedlyfor a predetermined number of times, and then dried. The sample obtainedwas spanned horizontally, and one water drop (0.04 cc) was added fromthe height of 1 cm, and the time until the water was completely absorbedby the sample, and reflected light could be no longer observed, wasmeasured.

(ii) Water absorption measurement method

The dried sample of knitted fabric was dipped in water for 30 minutes orlonger, and then dehydrated by a dehydrating unit of the electricwashing machine for domestic use for 5 minutes. The water absorption wasdetermined from the weight of the dried sample and the weight of thesample after dehydration, according to the following formula.$\text{Water absorption} = \frac{\text{~~Sample weightafter dehydration} - \text{Dried sample~~~~~weight}}{{Dried}\quad {sample}\quad {weight}\quad (\%)}$

(iii) Method of assaying level of isosorbide nitrate in blood

After a separation of the plasma from 3 ml of sampled blood, it wasextracted with 4 ml of N-hexane and concentrated, followed by anaddition of ethyl acetate to 100 μl, which was then quantitated byGC-ECD.

(iv) Measurement method of BN level in blood

After a separation of plasma from 1 ml of sample blood, the BN wasquantitated by the GC-MS method as described in the Journal ofChromatography, 338 (1985), pp. 89-98.

The hollow fiber and the tackifier solution used in the Examples wereprepared according to the following methods.

(1) Hollow fiber sample (1)

An amount of 297 parts of dimethyl terephthalate, 265 parts of ethyleneglycol, 53 parts (11.7 mole % based on dimethyl terephthalate) of sodium3,5-di(carbomethoxy)benzenesulfonate, 0.084 part of manganese acetatetetrahydrate, and 1.22 parts of sodium acetate trihydrate were chargedinto a glass flask equipped with a rectification tower, subjected to anesterinterchange reaction, and the reaction product after thetheoretical amount of methanol was distilled out was charged into apolycondensation flask equipped with a rectification tower. As thestabilizer, 0.090 part of an aqueous 56% normal phosphoric acid wasadded, 0.135 part of antimony trioxide was added as thepoly-condensation catalyst, and the reaction was carried out at 275° C.under normal pressure for 20 minutes, under a reduced pressure of 30mmHg for 15 minutes, under a high vacuum for 100 minutes, and under afinal inner pressure of 0.39 mmHg. The copolymerized polymer obtainedwas found to have an intrinsic viscosity of 0.402 and a softening pointof 200° C. After completion of the reaction, the copolymer was formedinto chips in a conventional manner.

After 15 parts of the chips of the copolymer and 85 parts of chips of apolyethylene terephthalate having an intrinsic viscocity of 0.640 weremixed in a Nauta mixer (Hosokawa Tekkosho) for 5 minutes, the mixturewas dried in a nitrogen gas stream at 110° C. for 2 hours, and furtherat 150° C. for 7 hours and formed into chips by melting and kneading ina twin screw extruder at 285° C. The chips had an intrinsic viscosity of0.535 and a softening point of 261° C.

The chips were dried in a conventional manner, and spun by aconventional procedure using a spinning orifice having a circular slitwith an arcuate opening 0.05 mm in width and 0.6 mm in diameter, with atwo parts being closed, to prepare a hollow fiber with ratio of theouter diameter to the inner diameter thereof of 2:1 (hollow ration 25%). The original fiber was 300 denier/24 filaments, and the originalfilament was stretched in a conventional manner at a stretching degreeof 4.2-fold to obtain a multi-filament of 71 denier/24 filaments. Themulti-filament was formed into a knitted cloth (abbreviated as greencloth), scoured and dried in a conventional manner, followed bytreatment with an aqueous 1% caustic soda at boiling point for 2 hoursto obtain a cloth thinned 15% of its weight by an alkali treatment of15%, a water absorption speed of 3 seconds, and a water absorption of80%. The knitted fabric obtained was stretched 1.5-fold in thelongitudinal direction, and heat set at 100° C. for one minute to obtaina knitted fabric with a weight per unit area of 38 g/m². The knittedfabric had loop numbers of 7/cm and 14/cm in the longitudinal andlateral directions respectively.

The fiber obtained was found to be a hollow fiber having fine poresscattered over the whole surface thereof extending toward the axis ofthe hollow fiber and at least some of which were channeled to the hollowportion of the fiber.

(2) Hollow fiber sample (2)

The knitted cloth obtained in the preparation of the hollow fiber sample(1) which was not subjected to the alkali treatment, and was a knittedfabric with a water absorption speed of 230 seconds and an absorptionratio of 38%. The weight per unit area of the knitted fabric obtained byheat as in the case of the hollow fiber sample (1) is 45 g/cm², and thesum of the loop numbers was the same as for the hollow fiber sample (1).

This hollow fiber had no pores extending therethrough in the outerperipheral direction.

(3) Tackifier solution (1)

An amount of 97.4 parts of 2-ethylhexyl acrylate, 2.5 parts ofmethacrylic acid, 0.1 parts of a polyethylene glycol (the degree ofpolymerization 14) dimethacrylate, 1.0 part of benzoyl peroxide, and 100parts of ethyl acetate were charged into a reactor having a refluxcondenser and a stirrer, and polymerization was continued under anitrogen atmosphere at 60° C. while slowly stirring the mixture for 9hours. The polymerization conversion was found to be 99.9%.

Then 500 parts of ethyl acetate were added to the polymer solution, tocontrol the solid concentration to about 20%.

Example 1-1

After 13 parts of isosorbide nitrate (ISDN) were added to 500 parts of atackifier solution (1) with a solid concentration of 20%, the solutionwas coated on a silicon-coated release paper to a thickness after dryingof 20 μm, and dried at 70° C. for 2 minutes, and at 110° C. for 3minutes. The residual amount of ethyl acetate in the tackifier layerobtained was 49 ppm, and the ISDN content 2.4 g/m². The tacky layercontaining the ISDN was divided into three, to obtain 3 tackifier layerswith the same composition (called tackifier layer d₁, tackifier layerd₂, and tackifier layer b).

Next, a film comprising a polyethylene terephthalate and having athickness of 3.5 μm (see “a” of FIG. 1) was pressure adhered on onesurface of the tackifier layer b, and the hollow fiber sample (1) (see“c” of FIG. 1) was pressure adhered on the free surface of saidtackifier layer b. The tackifier layer d₁ was then pressure adhered onthe free surface of the hollow fiber sample (1), and further, thetackifier layer d₂ was pressure adhered on the free surface of saidtackifier layer d₁, to obtain a plaster agent raw fabric containing 8.4g/m² of ISDN and 45 ppm of a residual solvent.

The thickness of the tackifier layer on the backing side of the presentplaster agent was 20 μm (see “b” of FIG. 1) and the thickness of thetackifier layer on the human skin side was 40 μm (see “d” of FIG. 1).

This plaster agent raw fabric was cut to a size of 2 cm×2 cm andplastered on the depilated part of the back of a depilated rat weighingabout 180 g, and blood was sampled at predetermined times to measure theISDN in the plasma. The results are shown in Table 1-1.

Comparative Example 1-1

After 16 parts of ISDN were added to 500 parts of a tackifier solutionwith a solid concentration of 20%, the solution was coated on asilicon-coated release film to a thickness of the tackifier layer afterdrying of 60 μ, and dried at 70° C. for 1 minute, and at 90° C. for 3minutes.

The residual amount of ethyl acetate in the tackifier obtained was 153ppm, and the content of ISDN was 8.7 g/m². When the drying temperatureswere made 90° C. for 1 minute and 130° C. for 3 minutes, to reduce theresidual amount of ethyl acetate, the content of ISDN became 8.1 g/m².The residual ethyl acetate at this time was 79 ppm.

After a polyethylene terephthalate film with a thickness of 3.5 μm waspressure adhered on one surface of the tackifier, the composite was cutto a size of 2 cm×2 cm, and the plastering test with a rat was conductedin the same manner as in Example 1-1.

The results are shown in Table 1-1. The present preparation was a flimsyfilm and was very difficult to handle.

Also, in all cases, erythema was clearly seen on the skin of the ratafter the test.

Comparative Example 1-2

A plaster agent was obtained in the same manner as in Example 1-1,except that the hollow fiber sample (2) was used instead of the hollowfiber sample (1), and the plastering test with a rat was conducted. Theresults are shown in Table 1-1.

The present preparation was stiff when compared with the plaster agentof Example 1-1, and erythema was observed on the skin of the rat afterthe test.

TABLE 1-1 ISDN level in rat blood (average value of n = 3) Unit (ng/ml)Plastering time (hrs) Preparation 0 1 3 8 24 Example 1-1 0 165 284 321169 Comparative Example 1-1 0 520 457 272 164 Comparative Example 1-2 0131 227 301 143

Examples 1-2-1-3 and Comparative Examples 1-3-1-5

Using the 71 denier/24 filaments shown in the preparation of the hollowfiber sample ( 1 ), knitted fabrics and woven fabrics with differentweights per unit area were prepared, and after scouring and dryingaccording to conventional processes, treated with an aqueous 1% causticsoda solution and at boiling point for 2 hours, to obtain knittedfabrics and woven fabrics thinned 15% of its weight by an alkalitreatment. Using these knitted and woven fabrics, the rat plasteringtests were conducted in the same manner as in Example 1-1, to obtain theresults shown in Table 1-2.

From Table 1-2, it is apparent that the plaster agents of the presentinvention exhibit an excellent slow release property. In contrast,Comparative Example 1-3 could obtain a desired level in the blood, andin Comparative Examples 1-4 and 1-5, erythema was observed on the skinof the rat.

TABLE 1-2 Estradiol level in rat blood (average value of n = 3) (Unit:ng/ml) Weight per unit area of knitted or woven Number of loops Knittedor fabric after (loops/cm) woven weight Longi- Plastering time (hrs)composition reduction tudinal Lateral Sum 0 1 3 8 24 Example 1-2 Knittedfabric 52  8 16 24 0 120 223 312 125 Example 1-3 ″ 26 12 14 26 0 208 317298 151 Comparative Knitted fabric 147  20 27 47 0  62 111  73  17Example 1-3 Comparative ″  9 18 20 38 0 381 440 213  85 Example 1-4^(*1)Comparative Woven fabric 34 — — — 0 201 298 255 164 Example 1-5^(*2)^(*1)Handelability of knitted fabric was poor. ^(*2)Preparation wasstiff without stretchability.

Test Example 1-1

A placebo preparation containing no ISDN was prepared under theconditions of Examples 1 -1 to 1-3 and Comparative Examples 1-1 to 1 -5,except that the production scale was reduced to one tenth. Further, aplacebo preparation of comparative Example 1-6 was made by using a 6 μpolyethylene terephthalate film instead of a 3.5 μ polyethyleneterephthalate film used in Comparative Example 1 - 1 . Each preparationwas cut to form a 3 cm ×3 cm sized plaster agent, and plastered in thecenter of the backs of five healthy human adults 20 to 30 years old andweighing from 56 to 72 kg, each sheet being chosen randomly from 9sheets in total of the respective plaster agents, and the skin rashstate 2 days after plastering was judged.

The judgment was 0 for no reaction, 1 for slight erythema, 2 for clearerythema, and 3 for the generation of papula, etc., and the resultsjudged by the total of the scores for the five members are shown inTable 1-3 .

TABLE 1-3 Human plastering test Skin rash (total score of Plasteringagent five members) Placebo of Example 1-1 2 Placebo of Example 1-2 2Placebo of Example 1-3 4 Placebo of Comparative Example 1-1 11 Placeboof Comparative Example 1-2 8 Placebo of Comparative Example 1-3 2Placebo of Comparative Example 1-4 7 Placebo of Comparative Example 1-510 Placebo of Comparative Example 1-6 13

From Table 1-3 , it can be clearly seen that the plaster agent of thepresent invention markedly reduces skin rash.

The sample of Comparative Example 1 -3 could not give a desired level inthe blood, as shown in Table 1-2.

Example 1-4

An ethyl acetate solution containing the tackifier prepared in the “( 3) tackifier solution ” as described above was coated on a silicon-coatedrelease film (film substrate was a polyethylene terephthalate with athickness of 75 μm) to a thickness after drying of 20 μm, and 40 μm,dried at 90 ° C. for 1 minutes and at 130 ° C. for 3 minutes, to obtaintwo kinds of tackifier layers, ( 1 ) with a thickness of 20 μm and ( 2 )with a thickness of 40 μm. The residual solvent in the tackifier layerswas found to be 20 ppm or less.

On one surface of a film of a polyethylene terephthalate with athickness of 3.5 μm, a width of 1000 mm, and a length of 100 m wasadhered the trackifier layer ( 1 ) with a width of 980 mm, residualethyl acetate of 22 ppm, a thickness of 20 μm, and a length of 100 m,and then on the tackifier layer ( 1 ) was pressure adhered the hollowfiber sample ( 1 ) with a width of 1000 mm and a length of 100 m. Thesurface of the hollow fiber sample ( 1 ) was placed in continuouscontact with an acetone solution containing 30% by weight of ISDN, touniformly impregnate the acetone solution over substantially the wholesurface thereof. By passing the band-shaped laminate impregnated withacetone solution thus obtained through air stream at room temperaturefor 5 minutes, the acetone solvent was substantially completely removed,to give a laminate containing 9 g/m ² of ISDN. The ISDN-impregnatedlaminate was wound up tightly into a roll, around a paper tube having aninner diameter of 7.6 cm and a width of 1000 mm.

After the roll-shaped ISDN-impregnated knitted fabric laminate waspackaged with an aluminum foil having a thickness of about 100 μm, thepackage was heated under a constant temperature of 70 ° C. for 24 hours.Due to this heating operation, almost all of the ISDN in the hollowfiber sample was migrated into the tackifier layer ( 1 ), as confirmedby sampling.

On the free surface of the hollow fiber sample ( 1 ) of theISDN-impregnated knitted fabric laminate after heating were pressureadhered a new tackifier layer ( 2 ) with a residue of ethyl acetate of38 ppm, a thickness of 40 μm, a width of 980 mm, and a length of 100 m,to obtain a plaster agent raw fabric. The residual ethyl acetate in theraw fabric was 18 ppm, based on the tackifier.

The plaster agent raw fabric was cut to a size of 2 cm ×2 cm, plasteredon the depilated part of the back of a rat weighing about 180 g, andblood was sampled at predetermined times for a measurement of the ISDNin the plasma. The results are shown in Table 1-4.

Example 1-5

The plaster agent raw fabric obtained in Example 1-4 was cut to 2 cm ×2cm, and heat sealed in an aluminum bag, followed by a heat treatment at40 ° C. for 2 days. The plaster agent obtained was plastered on thedepilated part of the back of a rat weighing about 180 g, and the bloodwas sampled at predeterminded times for a measurement of the ISDN in theplasma. The results are shown in Table 1-4.

Comparative Example 1-7

A plaster agent was obtained in the same manner as in Example 1-4,except that the hollow fiber sample (2) was used instead of the hollowfiber sample (1), and the plastering test with a rat was conducted. Theresults are shown in Table 1-4.

When the hollow fiber sample (2) was employed, an attempt was made toobtain a knitted fabric surface impregnated uniformly with acetonesolution the free surface of the knitted fabric of the hollow fibersample (2) by a continuous contact thereof with an acetone solutioncontaining 30% by weight on the surface of the knitted fabric, but thecontinuous system could not be employed because the hollow fiber sample(2) did not absorb the acetone solution. Accordingly, the acetonesolution was uniformly sprayed on the free surface of the hollow fibersample (2). At this time, the variance of the ISDN amount in the hollowfiber sample (2) was clearly larger by 2- to 3 -fold than when employingthe hollow fiber sample (1). Also, it must be carefully handled untilabout 30-50% or more of the whole amount of the acetone in the hollowfiber sample (2) impregnated with ISDN was evaporated, or the contentwas varied.

Also, after a complete evaporation of the acetone, crystals of the ISDNwere adhered to the hollow fiber sample ( 2 ), which became brittle andthick, and therefore, only a very weak tackiness was obtained in thepressure adhesion to the tacky layer ( 2 ), and thus it was not suitablefor a continuous industrial production.

TABLE 1-4 ISDN level in rat blood (average value of n = 3) Unit (ng/ml)Plastering time Preparation 0 1 3 8 24 Example 1-4 0 150 263 305 181Example 1-5 0 294 317 313 120 Comparative Example 1-7 0 125 236 289 176

Examples 1-6 and 1-7 and Comparative Examples 1-8 -1-10

Using the multi-filament of 71 deniers/ 24 filaments shown in the itemof preparation of the hollow fiber sample (1 ), knitted fabrics andwoven fabrics with different weights per unit area were prepared, andafter scouring and drying in a conventional manner, treated with anaqueous 1% caustic soda solution and at boiling point for 2 hours, toobtain knitted fabrics and woven fabrics thinned 15% of its weight by analkali treatment. Using these woven and knitted fabrics, the plasteringtests with rats were conducted in the same manner as in Examples 1-4, toobtain the results shown in Table 1-5.

TABLE 1-5 ISDN level in rat blood (average value of n = 3) (Unit: ng/ml)Weight per unit area of woven Number of loops Woven or or knitted ofknitted fabric knitted fabric after Longi- Plastering time (hrs)composition reduction tudinal Lateral Sum 0 1 3 8 24 Remarks Example 1-6Knitted fabric 52  8 16 24 0 121 195 272 112 Example 1-7 ″ 26 12 14 26 0200 307 312 160 Comparative Knitted fabric 147  20 27 47 0  52 101  67 15 Example 1-8 Comparative ″  9 18 20 38 0 362 402 320 101Handleability of knitted Example 1-9 fabric poor and variance greatComparative Woven fabric 34 — — — 0 193 282 267 198 Preparation had nostretchability Example 1-10 and was stiff

Example 1-8

A plaster agent raw fabric containing ISDN was obtained in the samemanner as in Example 1-4, except that a hollow fiber sample having ahollow ratio of 8%, thinned 22% of its weight by an alkali treatmentobtained in the preparation method of the hollow fiber sample (1 ) wasused in place of the hollow fiber sample (1 ).

Using the plaster agent raw fabric obtained, the ISDN in the plasma wasmeasured in the same manner as in Example 1-4, and as a result, theconcentrations in the blood were similarly changed and no skin rash orthe like was seen at the applied portion.

Example 2-1

After 2.5 parts of estradiol were added to 500 parts of a tackifiersolution with a solid concentration of 20%, the solution was coated on asilicon-coated release paper to a thickness after drying of 20 μm, anddried at 70 ° C. for 2 minutes, and at 110 ° C. for 3 minutes. Theresidual amount of ethyl acetate in the tackifier layer obtained was 39ppm, and the estradiol content was 1.5 g/m ² . The tacky layercontaining said estradiol was divided into three, to obtain 3 tackifierlayers with the same composition (called tackifier layer d ₁ , tackifierlayer d ₂ , and tackifier layer b).

Next, a film comprising a polyethylene terephthalate and having athickness of 3.5 μm (see “a ” of FIG. 1) was pressured adhered on onesurface of the tackifier layer b, and the hollow fiber sample ( 1 ) (see“c ” of FIG. 1) was pressure adhered on the free surface of saidtackifier layer b. The tackifier layer d ₁ was then pressure adhered onthe free surface of said hollow fiber sample ( 1 ), and further, thetackifier layer d ₂ was pressure adhered on the free surface of saidtackifier layer d ₁ , to obtain a plaster agent raw fabric containing1.6 g/m ² of estradiol and 34 ppm of a residual solvent.

The thickness of the tackifier layer (see “b ” of FIG. 1) on the backingside of the present plaster agent was 20 μm, and the thickness of thetackifier layer (see “d” of FIG. 1) on the human skin side was 40 μm.

This plaster agent raw fabric was cut to a size of 2 cm ×2 cm andplastered on the depilated part of the back of a depilated rat weighingabout 180 g, and blood was sampled at predetermined times to measure theestradiol in the plasma. The results are shown in Table 2-1.

Comparative Example 2-1

After 2.5 parts of estradiol were added to 500 parts of a tackifiersolution was a solid concentration of 20%, the solution was coated on asilicon-coated release film to a thickness of the tackifier layer afterdrying of 60 μm, and dried at 70 ° C. for 1 minute, and at 90 ° C. for 3minutes.

The residual amount of ethyl acetate in the tackifier obtained was 172ppm, and the content was 1.6 g/m ² . When the drying temperatures weremade 90 ° C. for 1 minute and at 130 ° C. for 3 minutes, to reduce theresidual amount of ethyl acetate, the content of estradiol became 1.6g/m ² . The residual ethyl acetate at this time was 83 ppm.

After a polyethylene terephthalate film with a thickness of 3.5 μm waspressure adhered on one surface of the tackifier, the composite was cutto a size of 2 cm ×2 cm, and the plastering test with a rat wasconducted in the same manner as in Example 2-1.

The results are shown in Table 2-1. The present preparation was a flimsyfilm and was very difficult to handle.

Also, in all the cases, erythema was clearly seen on the skin of the ratafter the test.

Comparative Example 2-2

A plaster agent was obtained in the same manner as in Example 2-1,except that the hollow fiber sample (2 ) was used instead of the hollowfiber sample (1 ), and the plastering test with a rat was conducted. Theresults are shown in Table 2-1.

The present preparation was stiff when compared with the plaster agentof Example 2-1, and erythema was observed on the skin of the rat afterthe test.

TABLE 2-1 Estradiol level in rat blood (average value of n = 3) Unit(ng/ml) Plastering time (hrs) Preparation 0 1 3 8 24 Example 2-1 13 411607 599 183 Comparative Example 2-1 22 780 1003 566 114 ComparativeExample 2-2 22 344 540 656 128

Examples 2-2-2-3 and Comparative Examples 2-3-2-5

Using the 71 denier/24 filaments shown in the preparation of the hollowfiber sample (1 ), knitted fabrics and woven fabrics with differentweights per unit area were prepared, and after scouring and dryingaccording to conventional methods, treated with an aqueous 1% causticsoda solution and at the boiling point for 2 hours to obtain knittedfabrics and woven fabrics thinned about 15% of its weight by an alkalitreatment. Using these knitted and woven fabrics, the rat plasteringtests were conducted in the same manner as in Example 2-1, to obtain theresults shown in Table 2-2.

From Table 2-2, it is apparent that the plaster agents of the presentinvention exhibit an excellent slow release property. In contrast,Comparative Example 2-3 cannot obtain a desired level in the blood, andin Comparative Examples 2-4 and 2-5, erythema was observed on the skinof the rat.

TABLE 2-2 Estradiol level in rat blood (average value of n = 3) (Unit:ng/ml) Weight per unit area of knitted or woven Number of loops Knittedor fabric after (loops/cm) woven weight Longi- Plastering time (hrs)composition reduction tudinal Lateral Sum 0 1 3 8 24 Example 2-2 Knittedfabric 52  8 16 24 18 301 511 554 147 Example 2-3 ″ 26 12 14 26 24 500763 602 133 Comparative Knitted fabric 147  20 27 47 25 140 254 261  54Example 2-3 Comparative ″  9 18 20 38 11 615 912 519 123 Example2-4^(*1) Comparative Woven fabric 34 — — — 16 185 411 520 206 Example2-5^(*2) ^(*1)Handelability of knitted fabric was poor. ^(*2)Preparationwas stiff without stretchability.

Example 3-1

Into 100 parts of the acrylic tackifier solution (1) was added the wholeamount of a solution of 0.5 part of estradiol (E ₂ ) dissolved in 15parts of methanol, and further, 25 parts of ethyl acetate were added,followed by stirring, to obtain a uniform dope. The dope was coated on asilicon-coated release paper to a thickness after drying of 20 μm and 40μm, and dried at 90 ° C. for 1 minute and at 120 ° C. for 2 minutes, toobtain an acrylic tackifier layer containing 2.5% by weight of E ₂.

The residual solvents in the tackifier layers having a thickness of 20and 40 μm were found to be 41 ppm and 123 ppm, respectively, and thewater contents thereof were 0.7% by weight.

A polyethylene terephthalate film (see “a ” of FIG. 1) with a thicknessof 3.5 μm was pressure adhered onto one surface of the 20 μm tackifierlayer obtained (“b ” in FIG. 1), the knitted fabric (see “c ” in FIG. 1)of the hollow fiber sample (3 ) of Reference example pressure wasadhered onto the free surface opposite to said tackifier layer, and thetackifier layer (see “d ” of FIG. 1) with a thickness of 40 μm asdescribed above was pressure adhered onto the free surface of theknitted fabric, to give a plaster agent raw fabric. After the plasteragent raw fabric was cut to a size of 5 cm ², it was dehumidifiedaccording to the method described below, and packaged. That is, thefabric was heated under a pressure of about 5 mmHg or lower, for 24hours, in a vacuum dryer. After being taken out from the vacuum dryer,while avoiding water absorption, the fabric was placed in a bag ofaluminum laminated with polyethylene and having a thickness of thealuminum foil of 12 mm, and heat sealed.

The E ₂ content in the plaster agent thus obtained was 2.5% by weightbased on the tackifier, the water content was 0.17% by weight based onthe tackifier layer, and the residual solvent was 20 ppm. The plasteragent had a water content of 0.17% after an elapse of 3 months under atemperature of 40 ° C. and a humidity of 75% RH, which are theconventional short period stability evaluation conditions ofpharmaceuticals.

The plaster agent after an elapse for 3 months under 40 ° C. and 75% RHwas plastered onto the back of a 7 weeks old male hairless rat depilatedby an electric hair clipper (n =5 ), the blood was sampled 2 hours, 4hours, 8 hours, and 24 hours after the plastering, and a serum wasseparated for an assay of E ₂ in the serum by radio-immunoassay.

The results of the levels in the blood are summarized in Table 3-1, interms of the maximum level in blood Cmax and AUC, which is the areaunder the curve of the level in the blood vs time.

Examples 3-2 -3 -5, Comparative Examples 3-1 -3 -5

Plaster agents were obtained, in the same manner as in Example 3-1,except for changing the E ₂ concentration and the water content bychanging the amount of estradiol (E ₂ ) employed, and changing thedehumidification conditions after cutting the plaster agent raw fabric,and after an elapse of 3 months at 40 ° C. and a humidity of 75% RH,tests were conducted with a hairless rat and the results were as shownin Table 3-1.

TABLE 3-1 Evaluation results of plaster agents (stored at 40° C. and 75%RH for 3 months) Tackifier layer composition E₂ concen- Water Level inblood tration content AUC Cmax (% by weight) (% by weight) (pg.hr/ml)(pg.hr/ml) Example 3-1 2.5 0.17 11383 1032 Example 3-2 0.6 0.38 7251 488Example 3-3 0.6 0.29 12263 1116 Example 3-4 0.6 0.45 6606 540 Example3-5 4.5 0.09 10005 782 Comparative 0.3 0.11 3640 232 Example 3-1Comparative 0.6 0.82 3565 236 Example 3-2 Comparative 2.5 0.69 4620 276Example 3-3 Comparative 4.5 0.62 4106 341 Example 3-4 Comparative 7.00.14 3106 180 Example 3-5 Comparative 2.5 1.90 1648 79 Example 3-6

From Table 3-1, it can be clearly seen that the plaster agent of thepresent invention has an excellent stability with a lapse of time, andexhibits excellent AUC and Cmax effects.

Comparative Example 3-6

The plaster agent with an E ₂ content of 2.5% by weight and a watercontent based on the tackifier layer of 0.17% obtained in Example 3-1was placed, without aluminum bag packaging, under the conditions of 40 °C. and 75% RH for 2 weeks. The water content was 1.9% and E ₂ was foundto be agglomerated in the tackifier layer, and the plastering testsresults with hairless rat were very bad, as shown in Table 3-1.

Example 3-6

The plaster agent with an E ₂ content of 2.5% by weight and a watercontent based on the tackifier layer of 0.17% obtained in Example 3-1was packaged in an aluminum bag. At this time, the thickness of thealuminum foil employed in Example 1 was not 12 mm but 7 mm, and 20 bagseach containing one sheet of plaster agent per bag were obtained by heatsealing at a seal width of 6 mm, and the change in average water contentwith a lapse of time under the conditions of 40 ° C. and 75% RH wasexamined on an average value of 5 sheets each time.

The water content was 0.23% by weight after one month, 0.31% by weightafter two months, 0.38% by weight after three months, and 0.44% byweight after 4 months, with the variance being great.

Example 3-7

The plaster agent with an E ₂ content of 2.5% by weight and a watercontent based on the tackifier layer of 0.17% obtained in Example 3-1was placed in the aluminum bag used in Example 3-6, and 1 g of drysilica gel was sealed together with the plaster agent, followed by heatsealing in the same manner as in Example 3-6, to obtain 20 bags ofplaster agents. When the change in the water content in the tackifierlayer of the plaster agent was monitored in the same manner as inExample 3-6, the water content was 0.17% or less up to 4 months, withthe variance being extremely small.

Example 4-1

To a solution of 0.5 part of estradiol (E ₂ ) dissolved in 15 parts ofmethanol (Solution A), a solution of 0.2 part of a PVP having amolecular weight of 1,200,000 (G.A.F., K- 90 ) dissolved in 30 parts ofchloroform, and 100 parts of the acrylic tackifier solution (1 ) wereadded 55 parts of ethyl acetate, and the mixture was vigorously stirredto form a uniform dope. Then, the dope was coated on a silicon-coatedrelease paper to a thickness after drying of 40 μm, and dried at 90 ° C.for 20 minutes to obtain an acrylic tackifier layer containing E ₂ (2.5%by weight) and PVP (1% by weight).

The above-obtained two tackifier layers (see “b ” and “d ” of FIG. 1)having a thickness of 40 μm and containing E ₂ and PVP were prepared andthe hollow fiber sample (3 ) was sandwiched between the two tackifierlayers and laminated under pressure. After a polyethylene terephthalatefilm (see “a ” of FIG. 1) with a thickness of 3.5 μm was pressureadhered onto one whole surface of one surface of the free tackifierlayer, a plaster agent (E ₂ (2.5% by weight), PVP (1% by weight))obtained by cutting it to a size of 5 cm ² was evaluated as mentionedabove. The results are also shown in Table 4-1. The preparationaccording to the present invention sufficiently maintains theflexibility of the plaster, and further, has an excellenthandleablility.

TABLE 4-1 Evaluation results of plaster agents Level in blood (pg/ml)Concentration in Adhesive 0 hour State of skin plaster agent (%) forceafter 2 8 24 after removal of Test No. E₂ PVP (g/12 cm) plastering hourshours hours plaster agent Example 4-1 2.5 1 310 22 1350 1005 295 Goodwithout erythema

Example 5-1

Into 100 parts by weight of the tackifier solution (1 ) was added asolution of 1.5 parts of buprenorphin dissolved in a mixture of 15 partsof methanol and 270 parts of ethyl acetate, and further, a solution of0.2 part of HCO- 60 dissolved in 15 parts of ethyl acetate was added,followed by vigorous mixing and stirring, to obtain a uniform solution(dope).

The dope obtained was coated on a silicon-coated peeling sheet to athickness of the pressure sensitive tackifier layer containingbuprenorphin, after drying, of 30 μm, followed by drying at 50 ° C. for10 minutes, at 70 ° C. for 2 minutes, and at 50 ° C. for 120 minutes.The residual amount of ethyl acetate in the pressure sensitive tackifierlayer was found to be 46 ppm, and the content of the buprenorphin was2.9 g/m ² .

The pressure sensitive tackifier layer containing buprenorphin wasdivided into two, to obtain two pressure sensitive tackifier layers(called b and d) with the same composition.

Next, on one surface of the pressure sensitive tackifier layer b waspressure adhered a polyethylene terephthalate film with a thickness of3.5 μm, on the free surface of said pressure sensitive tackifier layer bwas pressure adhered the hollow fiber sample (1 ), and on the freesurface of said hollow fiber sample (1 ) (layer c) was pressure adheredthe pressure sensitive tackifier layer d. Further, on the free surfaceof said tackifier layer d was mounted a silicon-coated film as thepeeling sheet, to obtain a plaster agent raw fabric containing 2.9 g/m ²of buprenorphin, as shown in FIG. 1.

After said plaster agent raw fabric was cut to a circular shape with asize of 9 cm ² , it was plastered on the depilated part of the back of ahairless rat with a body weight of about 180 g, blood samples were takenat predetermined times, and the buprenorphin levels in the plasma weremeasured. The content in the present plaster agent was 2.6 g and thecontent ratio was 7.5% by weight. The results are shown in Table 5-1.

Example 5-2

According to the same procedure as in Example 5-1, except for using 1.6parts of buprenorphin hydrochloride in place of 1.5 parts ofbuprenorphin and a mixture of 0.2 parts of HCO- 60 and 0.2 parts ofdiisopropanolamine in place of 0.2 part of HCO- 60, a plaster agent rawfabric containing 2.8 g/m ² of buprenorphin hydrochloride as calculatedon buprenorphin and 43 ppm of residual ethyl acetate in the pressuresensitive tackifier layer was obtained.

After the plaster agent raw fabric was cut to a circular shape with asize of 9 cm ² , the hairless rat plastering test was conducted in thesame manner as in Example 5-1, to obtain the results show in Table 5-1.

The content and the content ratio of the present plaster agent werefound to be 2.5 mg and 7.5% by weight, respectively.

Example 5-3

According to the same procedure as in Example 5-2, except for using 0.2part of a polyvinyl pyrrolidone K- 90 in place of the mixture of 0.2part of HCO- 60 and 0.2 part of dissopropanolamine, a plaster agent rawfabric containing 2.8 g/m ² of buprenorphin hydrochloride as calculatedon buprenorphin and 37 ppm of residual ethy acetate in the pressuresensitive tackifier layer was obtained.

After the plaster agent raw fabric was cut to a circular shape with asize of 9 cm ² (buprenorphin content 2.5 mg, content ratio 7.5% byweight), the hairless rat plastering test was conducted in the samemanner as in Example 5-2, to obtain the results shown in Table 5-1.

Example 5-4

According to the same procedure as in Example 5-1, except for using 1.6parts of buprenorphin hydrochloride in place of 1.5 parts ofbuprenorphin and 0.2 parts of diisopropanolamine in place of 0.2 part ofHCO- 60 , a pressure sensitive tackifier layer containing buprenorphinhydrochloride with a thickness of 30 μm, containing 1.4 g/m ² ofbuprenorphin hydrocloride as calculated on buprenorphin, and 45 ppm ofresidual ethyl acetate in the pressure sensitive tackifier layer wasobtained, and then cut to a size of 3 ×3 cm ² (buprenorphin content 1.3mg, content ratio 7.5% by weight).

On one surface of said pressure sensitive tackifier layer with a size of9 cm ² was pressure adhered a film (C) of an ethylene-vinyl acetatecopolymer (vinyl acetate ratio 10%) with a size of 4 ×4 cm ² and athickness of 50 μm, to cover the whole surface, and further, a mixtureof ethanol and hydroxypropyl cellulose (90:10 ) was placed at a centralportion with a size of 3 ×3 cm ² on the free surface of saidethylene-vinyl acetate copolymer film, an ethylene-vinyl acetatecopolymer film (D) with a size of 4 ×4 cm ² and a thickness of 50 μm waslaminated with a 3.5 μm polyethylene terephthalate film and covered onthe whole surface thereof. The ethylene-vinyl acetate copolymer film (C)and the ethylene-vinyl acetate copolymer film (D) were shaped into a bagto enclose the ethanol and hydroxypropyl cellulose therein, and theedges of the four sides were heat sealed to a width of about 5 mm, sothat the ethanol and hydroxypropyl cellulose could not escape.

The results obtained by plastering buprenorphin hydrochloride having anethanol reservoir thus obtained, in the same manner as in Example 5-1are shown in Table 5-1. It was confirmed by the GC method that ethanolwas slowly released through the ethylene-vinyl acetate copolymer film,from the ethanol reservoir of this Example.

TABLE 5-1 BN level in rat blood (average value of n = 2) (Unit: ng/ml)Preparation (by use of Level in blood hollow fiber sample) 2 hours 8hours 24 hours Kind Content Absorption before after after after of BNContent^(*1) ratio^(*2) promoter^(*3) plastering plastering plasteringplastering Example 5-1 Free 2.6 7.5 HCO-60 (1) 0 6.8 11.2 8.0 HCLExample 5-2 salt 2.5 7.5 HCO-60 (1) 0 8.3 11.9 4.5 DIPA^(*4) Example 5-3″ 2.5 7.5 PVP K-90 0 3.0 6.8 2.2 Example 5-4 ″ 1.3 7.5 DIPA (1) 0 1.710.4 — Ethanol reservoir ^(*1)mg ^(*2)% by weight ^(*3)% by weight ofnumeral in bracket ^(*4)DIPA: diisopropanolamine

Example 5-5

In the same manner as in Example 5-1, except for not using HCO- 60 , aplaster agent with a size of 4.5 cm ² , a buprenorphin content of 1.3mg, and a content ratio of 7.5% by weight was obtained.

The preparation obtained was plastered onto the back of a depilatedhairless rat with a body weight of about 180 g, and 8 hours afterplastering, the plaster agent was removed. The buprenorphin amount inthe preparation after plastering was extracted with methanol and thequantitated by the HPLC method, and the buprenorphin amount absorbedduring 8 hours plastering was estimated. The results are shown in Table5-2.

Examples 5-6 -5-15

In the same manner as in Example 5-1, except for using buprenorphinhydrochloride in place of buprenorphin and the promoter shown in Table5-2in place of HCO- 60, a plaster agent with a size of 4.5 cm ², abuprenorphin content of about 1.3 mg, and a content ratio of 7.5% byweight was obtained.

For the plaster agents thus obtained, the plastering tests werepracticed in the same manner as in Example 5-5, and from thebuprenorphin concentration difference in the preparation before andafter plastering, the amount of buprenorphin absorbed was estimated toobtain the results shown in Table 5-2.

It can be seen that buprenorphin is better absorbed than buprenorphinhydrochloride. Also, the hydrochloride had a very low subcutaneousabsorption amount in the absence of absorption promoter. Nevertheless,when the preparations were plastered, the hairless rat exhibitedsymptoms which may be considered to be due to the pharmacological effectof buprenorphin, such as an extremely worsened response to external heatstimulation.

TABLE 5-2 Rat percutaneous absorption amount of BN (Unit: μg/8 hours)Absorption promoter Amount Percutaneous added Absorption PreparationCompound (%) amount Example 5-5 (BN free) None — 40 Example 5-6 (BN HClsalt) Propylene 1 132 glycol Example 5-7 (BN HCl salt) Tween^(R) 80 1250 Example 5-8 (BN HCl salt) Isopropyl 1 195 myristate Example 5-9 (BNHCl salt) Benzyl alcohol 1 201 Example 5-10 (BN HCl salt) Diisopropanol1 44 amine Example 5-11 (BN HCl salt) Menthol 5 55 Example 5-12 (BN HClsalt) Isosorbide 5 149 nitrate Example 5-13 (BN HCl salt) HCO-60 0.5 159Example 5-14 (BN HCl salt) HCO-60 1.0 139 Example 5-15 (BN HCl salt)None — 20

What is claimed is:
 1. A method of preparing a plaster agent comprising:laminating one tackifier layer (layer b), a knitted fabric having aweight per unit area of 10 to 100 g/m ² and a texture wherein the sum ofa number of loops in the longitudinal and lateral directions thereof is15 to 37 loops/cm (layer c) comprising hollow fibers having poresextending therethrough in the outer peripheral direction andsubstantially free from medicine and another tackifier layer (layer d)on one surface of a water impermeable or water semipermeable film (layera) in an order of layers a, b, c, d, and using a tackifier layercontaining at least one medicine selected from nitric acid esters,guayazulene, camphor, menthol, salicylic acid esters, hormones,analgesics and cardiac agents as at least one of said layer b and saidlayer d.
 2. A method of preparing a plaster agent as claimed in claim 1,wherein a laminate comprising layer b laminated on one surface of layera is prepared, a layer c is laminated on said layer b, and a layer d islaminated on said layer c.
 3. A method of preparing a plaster agent asclaimed in claim 1 or 2, wherein the medicine is at least onenon-vaporizable medicine selected from hormones, analgesics, and cardiacagents.
 4. A method of preparing a plaster agent comprising: (1 )impregnating a laminate having a water impermeable or watersemipermeable film (layer a), one tackifier layer (layer b) containingsubstantially no vaporizable medicine or containing a small amount of avaporizable medicine and laminated on the surface of said layer a, and aknitted fabric having a weight per unit area of 10 to 100 g/m² and atexture wherein the sum of a number of loops in the longitudinal andlateral directions thereof is 15 to 37 loops/cm (layer c) comprisingpores extending therethrough in the outer peripheral direction andsubstantially free from medicine internally thereof and laminated onsaid layer b with a drug solution obtained by dissolving the vaporizablemedicine in a volatile solvent on the surface of said layer c, (2 )subsequently heating said laminate while the surface of said layer c isnot in contact with the air, to thereby cause a migration of saidvaporizable medicine in said knitted fabric portion to said layer b, and(3 ) laminating a second tackifier layer (layer d), which may alsocontain said vaporizable medicine, on said layer c.
 5. A method ofpreparing a plaster agent as claimed in claim 4, wherein the medicine isat least one vaporizable medicine selected from nitric acid esters,guayazulene, camphor, menthol and salicylic acid esters.
 6. A method ofpreparing a plaster agent comprising: (1 ) impregnating a laminatehaving a water impermeable or water semipermeable film (layer a), onetackifier layer (layer b) containing substantially no vaporizablemedicine or containing a small amount of a vaporizable medicine andlaminated on the surface of said layer a, and a knitted fabric having aweight per unit area of 10 to 100 g/m² and a texture wherein the sum ofa number of loops in the longitudinal and lateral directions thereof is15 to 37 loops/cm (layer c) comprising pores extending therethrough inthe outer peripheral direction and substantially free from medicineinternally thereof and laminated on said layer b with a drug solutionobtained by dissolving the vaporizable medicine in a volatile solvent onthe surface of said layer c, (2 ) laminating a second tackifier layer(layer d), which may also contain said vaporizable medicine, on saidlayer c to obtain a laminate, and (3 ) heating said laminate to therebycause a migration of said vaporizable medicine in said knitted fabricportion to said layer b and/or said layer d.
 7. A method of preparing aplaster agent as claimed in claim 6, wherein the medicine is at leastone vaporizable medicine selected from nitric acid esters, guayazulene,camphor, menthol, and salicylic acid esters.
 8. A method of preparing aplaster agent as claimed in claim 1, wherein said nitric acid ester isisosorbide dinitrate, said hormone is at least one compound selectedfrom the group consisting of estradiol, estradiol benzoate, estradioldipropionate, estradiol valerate, and ethynyl estradiol, and saidanalgesic is buprenorphin.